The Familial Alzheimer's disease gene product Amyloid beta Precursor Protein (APP) undergoes extensive processing. APP cleavage by secretases has been studied in great detail because it generates Abeta peptides that are implicated in the pathogenesis of Alzheimer's disease. Recent data indicate that the intracellular domain of APP (AID), released together with Abeta, has signaling functions. AID can induce cell death, plays a role in the regulation of gene transcription and regulates calcium release from endoplasmic reticulum stores. We have found that AID can repress Notch-dependent transcription and that this restraint may be mediated by the interaction of AID with the Notch inhibitors Numb/Numblike (Nbl). Numb has also been involved in receptors endocytosis and endocytosis of APP is known to regulate APP processing. Based on these findings, we hypothesize that Numb/Nbl proteins mediate the inhibitory effect of AID on Notch signaling and regulate APP endocytosis and processing. In this application, we propose to study the role of Numb/Nbl proteins in inhibition of Notch by AID, in APP endocytosis and APP processing. Aside for their relevance to the biology of APP. these studies may have implications pertinent to the therapy and pathology of Alzheimer's disease. Drugs designed to lower Abeta production might also alter the levels of AID. Therefore a clear understanding of the biological functions of AID may help in predicting and preventing toxic effects due to alterations in AID production by these inhibitors. Furthermore, inhibition of Notch signaling by AID might accelerate the neurodegenerative process of Alzheimer's disease by enhancing synapse loss, neurite dystrophy and neuronal degeneration. Lastly, regulation of APP endocytosis and processing by Numb/Nbl proteins might provide potential new targets for compounds aimed to reduce Abeta production.